Salt form of tyrosine kinase inhibitor

Abstract

Provided are acid addition salts of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2 -dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide, wherein the salt comprising at least one of a number of salts including L-malate, hydrochloride, phosphate, L-tartrate, benzenesulfonate, sulfate, methanesulfonate, succinate, citrate, fumarate, p-toluenesulfonate, hydrobromate, L-mandelate, lactate, acetate or maleate salt. Also provided is a pharmaceutical composition comprising the salt compounds, and a method of treatment by administering a therapeutically effective amount of the salt compounds as preparation of medicaments.

The invention claimed is: 
     
       1. An acid addition salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide, wherein the salt comprises at least one of L-malate, citrate, hydrochloride, phosphate, or lactate salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide. 
     
     
       2. The salt of  claim 1 , wherein the salt comprises L-malate salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide. 
     
     
       3. The salt of  claim 1 , wherein the salt comprises citrate salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide. 
     
     
       4. The salt of  claim 1 , wherein the salt comprises hydrochloride salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide. 
     
     
       5. The salt of  claim 1 , wherein the salt comprises phosphate salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide. 
     
     
       6. The salt of  claim 1 , wherein the salt comprises lactate salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide. 
     
     
       7. A pharmaceutical composition, comprising the salt of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
       8. The pharmaceutical composition of  claim 7 , wherein the salt is the L-malate salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide. 
     
     
       9. A method of treating at least one of colon cancer, gastric cancer, lung cancer, leukemia, pancreatic cancer, bladder cancer, hepatocellular cancer, breast cancer, or ovarian cancer, comprising:
 administering a therapeutically effective amount of an acid addition salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide to a subject in need thereof, wherein the salt comprises at least one of L-malate, citrate, hydrochloride, phosphate, or lactate salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide. 
 
     
     
       10. The method of  claim 9 , wherein the salt comprises L-malate salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide. 
     
     
       11. A composition, comprising at least two of L-malate, hydrochloride, phosphate, citrate, or lactate salts of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide. 
     
     
       12. The salt of  claim 1 , wherein the salt has a solubility of at least 0.2361 mg/ml in water, substantially improved plasma exposure, and substantially improved therapeutical effect as compared with (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide. 
     
     
       13. The salt of  claim 12 , wherein the solubility is in a range of about 0.2361 to about 38.62 mg/ml, and wherein the salt has a plasma exposure (AUC) in a range of about 184.9 to about 1489.4 (μg/L*h). 
     
     
       14. The salt of  claim 13 , wherein the salt comprises L-malate and has a solubility of about 38.62 mg/ml and a plasma exposure (AUC) of about 1489.4 (μg/L*h). 
     
     
       15. The method of  claim 9 , wherein the method is for treating colon cancers, and wherein the therapeutically effective amount of an acid addition salt of (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide has a solubility of at least 0.2361 mg/ml in water, substantially improved plasma exposure, and substantially improved therapeutical effect as compared with (Z)—N-[2-(diethylamino)ethyl]-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indol-3-carboxamide.